Safety and efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology is independent of spheroid dose after 4 years

Abstract

Purpose The aim of this study was to investigate the effect of product dose in autologous chondrocyte implantation (ACI) for the treatment of full‐thickness cartilage defects of the knee and to assess its influence on clinical and morphological mid‐term outcome. Methods Seventy‐five patients were included in this single‐blind, randomised, prospective, controlled clinical trial. Patients were assigned randomly to three different dose groups [low (3–7 spheroids/cm2), medium (10–30 spheroids/cm2), or high (40–70 spheroids/cm2)] and assessed using standardised clinical and morphological scoring systems (KOOS, IKDC, MOCART) for 4 years following the intervention. Results The analysis population comprised 75 patients (22 women, 53 men) aged 34 ± 9 years. Defect sizes ranged from 2 to 10 cm2 following intraoperative debridement. The assessment of the primary variable ‘overall KOOS’ showed a statistically significant improvement, compared with baseline, for each dose group, i.e., at baseline the mean ‘overall KOOS’ scores were 60.4 ± 13.6, 59.6 ± 15.4, and 51.1 ± 15.4 for the low‐, medium‐, and high‐dose groups, respectively, and 57.0 ± 15.2 for ‘all patients’. After 48 months those values improved to 80.0 ± 14.7, 84.0 ± 14.9, and 66.9 ± 21.5 in the respective dose groups and 77.1 ± 18.6 for ‘all patients’. Pairwise comparisons of these dose groups did not reveal any statistically significant differences. Likewise, assessment of the subjective IKDC score revealed no statistically significant differences between the three dose groups up to the 48‐month visit. However, between 12 and 48 months there was a low, but steady, improvement in the low‐dose group and a substantial amelioration in the medium‐dose group. The mean MOCART total scores 3 months after treatment were 59.8 ± 10.9, 64.5 ± 10.3, and 64.7 ± 9.4 for the low‐, medium‐, and high‐dose groups, and 62.9 ± 10.3 for ‘all patients’; 48 months after treatment these were 73.9 ± 13.1, 78.0 ± 12.4, and 74.3 ± 14.0 for the respective dose groups and 75.5 ± 13.1 for ‘all patients’. Conclusions Results of this study confirm the efficacy and safety of the applied “advanced therapy medicinal product”; no dose dependence was found either for the incidence or for the severity of any adverse reactions. All doses applied in the present study led to significant clinical improvement over time and can therefore be regarded as effective doses. The influence of product doses in the range investigated seems to be low and can be neglected. Thus, the authorised dose range of 10–70 spheroids/cm2 confirmed by this clinical trial offers a broad therapeutic window for the surgeon applying the product, thereby reducing the risk of over‐ or underdosing. Level of evidence I.

Role of Matrix-Associated Autologous Chondrocyte Implantation with Spheroids in the Treatment of Large Chondral Defects in the Knee: A Systematic Review

“…The literature search yielded 34 publications in PubMed and 70 in Web of Science. After removing 29 duplicates and screening the titles and abstracts, the full texts of 21 publications were screened, after which 18 [7,[10][11][12][13][14][15][17][18][19][20][21][22][23][24][25][26][27] were included and 3 [28][29][30] were excluded due to the use of xenogeneic materials [28] or antibiotics [29] in the cell culture, or the spheroids were formed by pelleting cells with centrifugation [30]. Two additional articles [16,31] were identified from citations (Figure 2).…”

“…The phase II clinical trial was a prospective, single-blinded, multicenter, doseconfirmation study in which the safety and efficacy of three different doses of Spherox for the treatment of cartilage defects in the knee were investigated (ClinicalTrials.gov identifier: NCT01225575, EudraCt No. 2009-016816-20) [10][11][12]. The primary outcome was the increase in the overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12 months follow-up, which was improved from mean 57.0 ± 15.2 to 73.4 ± 17.3 (Table 3) [10].…”

Three-dimensional, Scaffold-Free, Autologous Chondrocyte Transplantation: A Systematic Review

“…The search included 10 studies 11 , 12 , 14 , 15 , 19 , 20 , 29 , 33 , 34 , 36 that fulfilled the inclusion criteria: 2 randomized controlled trials, 15 , 19 7 case series, 11 , 12 , 19 , 20 , 33 , 34 , 36 and 1 cohort study. 14 Of the 10 studies, 6 studies addressed ACT3D of articular cartilage defects in the knee joint, 11 , 14 , 15 , 29 , 33 , 34 and 4 publications investigated the outcome of ACT3D therapy in affected hip joints. 12 , 19 , 20 , 36 The mean defect size of the treated lesions ranged from 2 to 6 cm 2 .…”

“…33,34 ACT3D further proved to be a suitable therapy for children and adolescents with chondral defects. 14 In 2020, Niemeyer et al 29 published the 4-year outcomes of their European Medicines Agency (EMA)-driven, prospective, phase II study addressing the dose-dependent safety and efficacy of Chondrosphere. The study did not reveal any statistically significant differences between different concentrations of spheroids in the dose range of 10 to 70 spheroids/cm 2 .…”

“…Hoburg (2019) adults 14 92.9 ± 7.9 (n ¼ 30) Siebold (2018) 34 77.7 ± 14.6 (n ¼ 30) Siebold (2016) 33 79.0 ± 18.0 (n ¼ 31) Fickert (2012) 11 82. 34 84.2 ± 5.6 (n ¼ 30) Siebold (2016) 33 63.0 ± 18.8 (n ¼ 31) Fickert (2012) 11 64.0 (n ¼ 37) Weighted average 73.5 (n ¼ 147) KOOS (overall) Hoburg (2020) 15,28 83.2 ± 14.9 (n ¼ 48) Niemeyer (2020) 5,27,29 77. 34 used a maximum MOCART score of 85 rather than 100; to compare their results with those of the other studies, we used the percentage instead of the absolute value.…”